N-acyl-7-(n{41 -cycloalkyl-ureido-n{40 -sulfonyl)-isoquinolines and -benzazepines and alkali metal salts thereof

ABSTRACT

WHEREIN R1 is straight or branched alkyl of one to four carbon atoms, phenyl, alkoxy of one to three carbon atoms - phenyl, tolyl, trifluoromethyl-phenyl, monohalo-phenyl, dihalo-phenyl, 2methoxy-5-chlorophenyl, diphenyl, Alpha -naphthyl, 1,2,3,4tetrahydronaphthyl-(1), indanyl-(1) or benzoyl, R2 is n-butyl, cycloalkyl of five to eight carbon atoms, alkyl of one to two carbon atoms - cycloalkyl of five to eight carbon atoms, or adamantyl-(1), A is a carbon-to-carbon bond, alkylene of one to five carbon atoms or phenyl-alkylene of one to five carbon atoms, and N IS 1 OR 2, AS WELL AS ALKALI METAL AND ALKALINE EARTH METAL SALTS THEREOF; THE COMPOUNDS AND THEIR SALTS ARE USEFUL AS HYPOGLYCEMICS IN WARM-BLOODED ANIMALS.   Compounds of the formula

United States Patent [191 Grell et a1.

[ 1 Apr. 3, 1973 Inventors: Wolfgang ,Grell; Gerhart Griss; Manfred Kleemann; Eberhard Kutter', all of Biberach/Riss, Germany Boehi'inger ingelheim G. in. b. H., Ingelheim/ Rhine, Germany Filed: June 25, 1970 Appl. No.: 49,930

References Cited UNITED. STATES PATENTS 3/1963 Hoehn et al. ..260/326.l2 R 11/1968 Muller et al. ..260/553 D Primary ExaminerAlton D. Rollins Attorney-Hammond & Littell [57] ABSTRACT Compounds of the formula (i) A (H) SOz-NIICNIIR2 wherein R is straight or branched alkyl of one to four carbon atoms, phenyl, alkoxy of one to three carbon atoms phenyl, tolyl, trifluoromethyl-phenyl, monohalo-phenyl, dihalo-phenyl, 2-methoxy-5- chlorophenyl, diphenyl, a-naphthyl, l,2,3,4- tetrahydronaphthyl-( 1 indanyl-( 1) or benzoyl,

R, is n-butyl, cycloalkyl of five to eight carbon atoms, alkyl of one to two carbon atoms cycloalkyl of five to eight carbon atoms, or adamantyl-(l),

A is a carbon-to-carbon bond, alkylene of one to five carbon atoms or phenyl-alkylene of one to five carbon atoms, and

n is l or 2,

as well as alkali metal and alkaline earth metal salts thereof; the compounds and their salts are useful as hypoglycemics in warm-blooded animals.

8 Claims, No Drawings cycloalkyl-ureido-N'-sulfonyl)-isoquinolines This invention relates to novel N- acyl7-(N"- and benzazepines, as well as pharmaceutically acceptable alkali metal and alkaline earth metal salts thereof, and to a method of preparing these compounds.

More particularly, the present invention relates to a novel class of compounds of the formula R is straight or branched alkyl of one to four carbon' atoms, phenyl, alkoxy of one to three carbon atoms phenyl, 'tolyl, trifluoromethyl-phenyl, monohalo-phenyl, dihalo-phenyl, 2-methoxy-5- chlorophenyl, diphenyl, a-naphthyl, 1,2,15,4-

tetrahydronaphthyl-( 1 indanyl-( l or benzoyl,

R is n-butyl, cycloalkyl of five to eight carbon atoms, alkyl of one to two carbon atoms cycloalkyl of five to eight carbon atoms, or adamantyl-(l), f

A is a carbon-to-carbon bond, alkylene of one to five carbon atoms or phenyl-alkylene of one to five carbon atoms, and

n is 1 m2,

as well as non-toxic, pharmacologically acceptable alkali metal and alkaline earth metal salts thereof.

The compounds of the formula I above may be prepared by either of the following methods:

Method A reacting a sulfonamide of the formula S Or -N112 O=C=NR (m) wherein R has the same meanings as in formula I.

The reaction is carried out in the presence of an inert organic solvent and preferably in the presence of an inorganic or tertiary organic base, such as an alkali metal hydroxide or pyridine. Although the reaction will proceed, in principle, at room temperature, it is preferably-performed at elevated temperatures, especially between 50 and. 150C., because the reaction time at room temperature is unduly long.

It is most advantageous to first form an alkali metal salt of the sulfonamide II by reacting the same with an ethanolic solution of an alkali metal hydroxide, evaporating the reaction solution to dryness, and then reacting the residue with the isocyanate III.

Method B By reacting a sulfonyl-carbamic acid ester of the formula - wherein R,, A and n have the same meanings as in fo'r- I mula I and alk is lower alkyl, with a primary amine of the formula H -N R (v) wherein R has the same meanings as in formula I.

The reaction is carried out in the presence of an inert organic solvent at room temperature or elevated temperatures, preferably at a temperature between 50 and C.

Examples of suitable inert organic solvents for use in Methods A and B are dimethylformamide, diniethylsulfoxide and nitr'obenzene; these solvents exhibit the most advantageous solvent properties with respect to the starting materials.

If desired, a compound of the formula I obtained by method A or B may be converted into a non-toxic, pharmacologically acceptable alkali metal or alkaline earth metal salt thereof by conventional methods; for instance, by dissolving the free acid in a suitable inert solvent, such as ethanol, and adding thereto a solution of one equivalent of ,an alkali metal hydroxide or alkaline earth metal hydroxide. The sodium salts of the compounds of the formula I are particularly preferred.

The starting materials for methods A and B, i.e., the compounds of the formulas [I and IV are also novel, but they may be prepared by methods involving known chemical principles.

Thus, a sulfonamide of the formula II may be prepared by reacting 1,2,3,4-tetrahydro-isoquinoline- 7-sulfonamide or 2,3 ,4 ,S-tetrahydrol I-I-3- benzazepine-7-sulfonamide, i.e., formula (CHz)n (VI) wherein n is 1 or 2, with an acyl halide of the formula (VII) wherein Rand A have the same meanings as in formula I and Hal is halogen, in the presence of a basic organic solvent, such as pyridine; or alternatively with a carboxylic acid of the formula a compound of the wherein R A and n have the same meanings as in formula I, with ammonia.

A sulfonyl-carbamic acid ester of the formula IV may be prepared by reacting a sulfonamide of the formula II with an alkyl chloroformate of the formula Cl COO alk (X) wherein alk has the same meanings as in formula IV.

The compounds embraced by formula VI are not described in the literature and are therefore also novel. These sulfonamides may be prepared by chlorosulfonation of a compound of the formula wherein n is 1 or %;N reacting the reaction product with ammonia, and subsequently splitting off the acetyl group.

1,2,3,4-Tetrahydro-isoquinoline-7-sulfonamide, i.e., the compound of the formula VI wherein n is 1, may also be prepared from 2-acetyl-7-amino-1,2,3,4- isoquinoline, which is a known compound, by converting the amino group of the latter into the chlorosulfonyl group by means of a modified Sandmeyer Reaction [see H. Meerwein et al, Berichte 60, 841 (1957)], reacting the product with ammonia, and splitting off the 2-acetyl substituent with the aid of a dilute mineral acid.

Finally, the sulfochlorides embraced by formula IX, which are also new, may be prepared by replacing the 7-amino group of a compound of the formula wherein R A and n have the same meanings as in formula I, by the chlorosulfonyl group by means of a modified Sandmeyer Reaction (see above); or also by chlorosulfonation of a compound of the formula irk (Xlll) wherein R,, A and n have the same meanings as in formula I, pursuant to known methods.

The following examples describe the preparation of the novel starting compounds.

EXAMPLE A 1,2,3 ,4-Tetrahydro-isoquinoline-7-sulfonamide hydrochloride a. A solution of 175.2 gm (lmol) of 2-acetyl-1,2,3,4- tetrahydro-isoquinoline in 80 ml of chloroform was added dropwise to 844 gm (7.24 mols) of chlorosulfonic acid, while exteriorly cooling the latter on an ice/salt bath to maintain the internal temperature at between 8 and 15C. Thereafter, the reaction mixture was allowed to stand overnight at 20C., and was then slowly poured over a large amount of ice. The aqueous mixture was extracted with chloroform, and the chloroform phase was dried, filtered and evaporated. 232 gm of raw 2-acetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfochloride, having a honey-like consistency, were obtained.

b. The raw sulfochloride thus obtained was made less viscous by heating it, and was then stirred into 600 ml of concentrated aqueous ammonia. The mixture was stirred and kneaded for one hour more, and then the colorless precipitate which had formed was separated by vacuum filtration, washed several times with water and once with acetone, and finally dried at C. in a vacuum of 0.1 mm Hg. 172 gm of 2-acetyl-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide, m. p. 220224 C., of the formula were obtained. Analysis: C H N 0 S; mol. wt. 254.2

Calculated:C 51.97%;1-1 5.55%;N 11.02%

FoundzC 52.40%;1-1 5.79%;N 10.58%

c. 'A mixture of 172 gm of 2-acetyl-1,2,3,4- tetrahydro-isoquinoline-7-su1fonamide and 1.4 liters of semiconcentrated hydrochloric acid was refluxed for 3 hours. Toward the end, activated charcoal was added, and the mixture was filtered, while still hot, through a layer of infusorial earth. The filtrate was evaporated in vacuo until crystallization began, and then cooled. The crystalline precipitate was collected by vacuum filtration and dried, yielding gm of l,2,3,4-tetrahydroisoquinoline-7-sulfonamide hydrochloride, m. p. 212217C., of the formula Analysis: C H Cl N O S;mol. wt. 248.7

Calculated:C-43.50%;H5.27%;N1 1.24% Found:C-43.30%; H5.35%;N- 10.89%

The free base had a melting point of 176l 80C.

EXAMPLE B l ,2,3 ,4-Tetrahydro-isoquinoline-7-sulfonamide hydrochloride a. 7.61 gm (0.040 mol) of 2-acetyl-7-amino-1,2,3,4- tetrahydro-isoquinoline, m. p. 107108C. [literaturez m. p. 109-1 l 1C.; E. Ochiai and T. Nakagome, Chem. Pharm. Bull. (Japan) 6, 497 (1958)], were dissolved in 8.4 ml of concentrated hydrochloric acid and, at an internal temperature of no more than 5C., diazotized with a solution of 3.04 gm (0.044 mol) of NaNO, in 6 ml of water.

The resulting diazonium salt solution was admixed with 3.04 gm (0.032 mol) of anhydrous MgCl,, the mixture was heated to 30C. and it was quickly stirred into 40 ml of glacial acetic acid which had been saturated with SO, and contained 2.2 gm (0.0129 mol) of CuCl 21-1 0, also heated to 30C. By exterior heating, the internal temperature of the reaction mixture was raised to 48C., and it was stirred at that temperature for 25 minutes. After that time, the initially vigorous evolution of nitrogen is only very slight. The darkbrown reaction solution was diluted with 60 ml of water, and extracted with cold ether. The ethereal extract solution was washed with dilute aqueous sodium bicarbonate, then with an aqueous sodium carbonate solution having a pH of 8-9 and finally with water, dried over sodium sulfate, and evaporated to dryness in vacuo. 7.0 gm of raw 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfochloride, having a honey-like consistency, remained as a residue.

b. 30 ml of concentrated ammonia were poured over 6.2 gm (22.6 millimols) of the raw sulfochloride obtained in (a), and the mixture was kneaded for 1 hour on an ice bath. Thereafter, the resulting crystallizate was vacuum-filtered, and the filter cake was washed three times with water and then twice with acetone. 4.3 gm of 2-acetyl-l,2,3,4-tetrahydro-isoquinoline-7-sulfonamide, m.p. 223226C, were obtained. AnalysiszC l-l N- o s; mol. wt. 254.2

Calculated:C-51.97%;H-5.55%;N1 1.02%

c. A mixture of 4.0 gm of the sulfonamide obtained in (b) and 60 ml of aqueous HCl was refluxed for 2.5 hours, toward the end in the presence of some activated charcoal. Thereafter, the reaction mixture was filtered through infusorial earth, and the filtrate was evaporated to dryness in vacuo. The residue was recrystallized from methanol, yielding 3.3 gm of 1 ,2,3 ,4-tetrahydro-isoquinoline-7-sulfonamide hydrochloride, m. p. 215-218C.

Analysis:C H Cl N O S; mol. wt. 248.7

Calculated:C-43.50%;M5.27%;Nl 1.24%

Found:C43.60%;H-5.41%;N10.99%

EXAMPLE C 2-( 3 '-Phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonamide Three hundred seventy-three gm (2.2 mols) of hydrocinnamic acid chloride were added dropwise to a suspension of 548 gm (2.2 mols) of 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hydrochloride (m.p. 212-217C) in 4 liters of pyridine (distilled over BaO), while stirring and cooling the latter to prevent the internal temperature from rising above 15C. Thereafter, the reaction mixture was stirred for 4 hours at C, and then the pyridine was distilled off in vacuo. The slurry-like residue was stirred with 3 liters of water, vacuum-filtered, again stirred with 4 liters of water and again vacuum-filtered. The last filter cake was dried and recrystallized from a mixture of methanol and dimethylformamide (3:1), yielding 440 gm of 2-(3'- phenyl-propionyl)-l ,2,3 ,4-tetrahydro-isoquinoline-7- sulfonamide, m.p. 218222C, of the formula AnalysiszC H N o s; mol. wt. 344.4

Calculated:C 62.78%;1-1 5.85%;N 8.14% FoundzC 63.00%;H 5.80%;N 8.16%

EXAMPLE D 2-(2-Phenyl-propionyl)-1,2,3,4-tetrahdyro-isoquinoline-7-sulfonamide 13.1 gm (0.1 1 mol) of freshly distilled thionyl chloride were slowly added dropwise to a mixture of 15.0 gm (0.10 mol)-of hydratropic acid, 24.9 gm (0.10 mol) of l,2,3,4-tetrahydro-isoquinoline-7-su1fonamide hydrochloride (m.p. 212217C) and 250 ml of pyridine (distilled over BaO), while maintaining the internal temperature of the mixture between 5 and 7C. Thereafter, the reaction mixture was stirred overnight at 20C, and then the pyridine was distilled off in vacuo. The greasy residue was stirred with water, the solid product formed thereby was collected by vacuum filtration, the filter cake was briefly boiled with ethylacetate, the mixture was allowed to cool, and the solid phase was separated by vacuum filtration, washed with ethylacetate, and dried at C in a vacuum of 20 mm Hg. 19.2 gm of 2-(2'-phenyl-pr0pionyl)-l,2,3,4- tetrahydro-isoquinoline-7-sulfonamide, m.p. 199-201 C, of the formula were obtained.

Analysis:C I-l N O S; mol. wt. 344.4

Calculated:C 62.78%;H 5.85%;N 8.13% Found:C --62.80%;H 5.93%;N 8.03%

EXAMPLE E sulfonamide (m.p. 222-227C), 33.2 gm (0.24 mol) of potassium carbonate, 26.0 gm (0.24 mol) of ethyl chloroformate and 350 ml of anhydrous acetone was refluxed for 24 hours. Thereafter, the reaction mixture was filtered, the filtrate was evaporated in vacuo, and the residue (31 gm) was dissolved in chloroform. THe resulting solution was extracted several times with dilute sodium hydroxide (pH 8-9), the combined aqueous alkaline extract solutions were made acid with hydrochloric acid and then extracted with chloroform, and the chloroform extract was dried and evaporated, leaving 12.9 gm of raw N-[2-(3-phenyl-propionyl)- 1 ,2,3 ,4-tetrahydro-isoquinoline-7-sulfonyl -carbamic acid ethyl ester (solidified foam; thin-layer chromatographically uniform).

The chloroform solution, which had been extracted with aqueous alkali as described above, was dried and evaporated, leaving 18.2 gm of raw N,N-bis-earbethoxy-2-( 3 '-phenyl -propionyl)-l ,2,3 ,4-tetrahydro-isoquinoline-7-sulfonamide having a honey-like consistency. This product was admixed with an ethanolic solution of three equivalents of sodium hydroxide and a little water (exothermic reaction), the solution was evaporated in vacuo, and the residue was treated twice with hot ethanol, i.e., by adding a little ethanol thereto and then boiling off the alcohol. The residue -phenyl-propionyl)- dissolved in hot water, the resulting alkaline solution was extracted with chloroform, made acid with hydrochloric acid and again extracted with chloroform.

Evaporation of the combined chloroform extracts yielded an additional 1 1.4 gm of the desired carbamic acid ester.

The two batches of recovered raw product (1 1.4 gm 12.9 gm) were combined and recrystallized from ethylacetate/ether, yielding 18.25 gm of colorless N-[2- (3 '-phenyl-propionyl)-l ,2,3 ,4-tetrahydro-isoquinoline- 7-sulfonyl1-carbamic acid ethyl ester, m.p. 138l4lC (decomp.), of the formula Analysis:C ,H N O S:mol. wt. 416.5 Calculated:N 6.73%;S 7.52% FoundzN 6.77%;S 7.73%

EXAMPLE F Evaporation of each of the chloroform extract solutions yielded 3.5 gm and 8.1 gm, respectively, of the raw product.

The 3.5 gm batch obtained from the chloroform extraction of the aqueous alkaline solution was admixed with sodium hydroxide and ethanol, the mixture was evaporated at 60C in a rotation evaporator, the residue was taken up in water, and the resulting alkaline solution was extracted with chloroform, then made acid with hydrochloric acid, and the acid solution was again extracted with chloroform, and this last acidic chloroform extract was evaporated, yielding 2.7 gm of raw product which were combined with the 8.1 gm of raw productobtained from the previous acidic chloroform extract. The raw product was dissolved in ethanol, and the solution was treated with activated charcoal, filtered and dried, yielding 9.2 gm of the chromatographically uniform, foam-like compound named in the heading of this example.

EXAMPLE G N-[2-( 3 '-phenyl-butyryl )-1 ,2,3 ,4-tetrahydro-isoquinoline-7-sulfonyl]-carbamic acid ethyl ester A mixture consisting of 21.5 gm (0.06 mol) of 2-(3'- phenyl-butyryl)- 1 ,2,3 ,4-tetrahydro-isoquinoline-7-sulfonamide (m.p. 164-166C), 26.1 gm (0.24 mol) of ethyl chloroformate, 33.2 gm (0.24 mol) of potassium carbonate and 600 ml of anhydrous acetone was refluxed for 32 hours. Thereafter, the reaction mixture was worked up as described in Example F. The two acidic chloroform extracts yielded 11.6 gm and 10.2 gm of raw product, respectively, which were combined and recrystallized from ethylacetate/ether. 16.0 gm of uniform N-[2-( 3 -phenyl-butyryl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester, m.p. l05l08C, were obtained. Analysis:C H N O -,S;mol.wt. 430.5

Calculated:C 61.39%;H 6.09%;N 6.51% FoundiC 61.20%;H 6.07%;N 6.68%

EXAMPLE H N-[2(2-p-Chlorophenyl-propionyl)-1,2,3 ,4- tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester A mixture consisting of 10.35 gm (27.4 millimols) of 2-(2'-p-chlorophenyl-propionyl)-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide (m.p. 147150C), 12.2 gm (112 millimols) of ethyl chloroformate, 15.5 gm (112 millimols) of potassium carbonate and 200 ml of anhydrous acetone was refluxed for 43 hours. Thereafter, the undissolved components were separated by vacuum filtration, the filtrate was evaporated, and the residue was dissolved in 2 N sodiurn hydroxide. The resulting aqueous alkaline solution was extracted with chloroform, made acid with hydrochloric acid and again extracted with chloroform. The chloroform extracts were each evaporated, yielding 15.6 gm and 0.1 gm, respectively, of the raw product. The 15.6 gm-batch obtained from the chloroform extract of the alkaline solution was taken up in a mixture of chloroform and dilute hydrochloric acid, and the chloroform phase was separated and evaporated, leaving 12.7 gm of a yellowish, foamy product which was purified by column -chromatography on silicagel (solvent system cyclohexanezacetonezglacial acetic acid 60:20:04). 8.0 gm of uniform, glassy N-[2-(2'-p chlorophenyl-propionyl)- l,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester (lR-spectrum peak at 1,760 cmfor EXAMPLE I 2-( 2 -p-Bromophenyl-propionyl)-1,2,3 ,4-tetrahydroisoquinoline-7-sulfonamide A solution of 7.80 gm (31.4 millimols) of l,2,3,4- tetrahydro-isoquinoline-7sulfonamide hydrochloride, 7.20 gm (31.4 millimols) of p-bromo-hydratropic acid, 3.18 gm (31.4 millimols) of triethylamine and 7.22 gm (62.8 millimols) of N-hydroxy-succinimide in 500 ml of anhydrous dimethylformamide was admixed at -22C with a solution of 12.96 gm (62.8 millimols) of dicyclohexyl-carbodiimide in 83 ml of dimethylformamide. The mixture ,was allowed to stand for 2 hours at -22C and then for 20 hours at 20C, whereupon the precipitate formed during that time was separated by vacuum filtration, and the filtrate was evaporated in vacuo at 12 mm Hg. The residue was dissolved in ethylacetate, and the solution was extracted with aqueous sodium bicarbonate, then with 2 N hydrochloric acid and finally with water. The ethylacetate solution was dried, filtered and evaporated, leaving as a residue 13 gm of the raw reaction product which was purified by column-chromatography on silicagel (solvent system cyclohexane:acetone 3:2). 5.2 gm of 2-(2-pbromophenyl-propionyl)-l ,2,3 ,4-tetrahydro-isoquinoline-7-sulfonamide, m.p. 146-148C (recrystallized from ethylacetate), of the formula were obtained.

Analysiszc l-l Br N O S;mol. wt. 423.4

CalculatedzC 51.07%;1-1 4.52%;N 6.62% Found:C 51.30%;H 4.38%;N 6.74%

EXAMPLE J 2( 2-p-Chlorophenylpropionyl)- l ,2,3 ,4-tetrahydroisoquinoline7-sulfonamide Fourteen gm (66 millimols) of 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide were dissolved in 850 ml of hot anhydrous dioxane. While the solution was still warm, 12.2 gm (66 millimols) of p-chloro-hydratropic acid were added thereto, and the mixture was cooled to 10C. At that temperature, a solution of 14.9 gm (72 millimols) of dicyclohexyl-carbodiimide in 70 ml of dioxane was added over a period of 10 minutes; after minutes the mixed solution turned cloudy, and a colorless precipitate began to separate out. The reaction mixture was allowed to stand for 16 hours at 20C and was then vacuum-filtered, and the filtrate was evaporated in a vacuum of 12mm Hg. The residual light yellow, viscous oil (37 gm) was taken up in a large amount of chloroform, and the solution was extracted with 2 N sodium hydroxide until no more sulfonamide could be chromatographically detected in the organic phase. The sodium hydroxide extracts were combined and stirred into a mixture of ice and hydrochloric acid. The acid aqueous mixture was again extracted with chloroform, and the extract was evaporated, yielding as the residue 17.4 gm of raw product which was purified by column-chromatography on silicagel (solvent system, cyclohexane:acetonezglacial acetic acid 60:40:04). The purified product was recrystallized from ethylacetate, yielding 10.3 gm of colorless 2-(2'- p-choropheny1-propionyl)- l ,2,3 ,4-tetrahydro-isoquinoline-7-sulfonamide, m.p. 147-150C. Analysis:C 1-I,,ClN O S;mo1. wt. 378.9

CalculatedzC 57.06%;1-1 5.05%;N 7.39%

Found:C 56.95%;1-1 5.18%;N 7.20%

EXAMPLE K 3-(2'-p-Bromophenyl-propionyl)-2,3,4,5-tetrahydro- 1H-3 benzazepine-7-sulfonamide Solvent-free p-bromo-hydratropic acid chloride, prepared from 8.0 gm (35 millimols) of p-bromohydratropic acid and SOCl in chloroform, was added at 5C to a solution of 7.92 gm (35 millimols) of 2,3,4,5-tetrahydro-l l-l-3benzazepine-7sulfonamide in 100 ml of anhydrous pyridine, and the mixture was allowed to stand overnight at 20C. Thereafter, the pyridine was distilled off in vacuo, the residue was stirred with aqueous hydrochloric acid and collected by vacuum filtration, the filter cake was dissolved in hot 2 N sodium hydroxide, and the alkaline solution was extracted with chloroform. The alkaline aqueous phase was stirred into a mixture of ice and hydrochloric acid, the acid aqueous solution was again extracted with chloroform, and the chloroform extract solution was thoroughly extracted with aqueous sodium bicarbonate and then with water. Evaporation of the chloroform phase yielded 7.9 gm of foamy 3-(2-p-bromophenylpropionyl)-2,3 ,4,5-tetrahydro-1H-3-benzazepine-7- sulfonamide of the formula Calculated:C 52.16%;H 4.84%;N 6.41% I Found:C 52.00%;H 4.61%;N 6.39%

EXAMPLE L 2,3,4,5-Tetrahydro-1H-3benzazepine-7-sulfonamide a. 130.6 gm (0.688 mol) of 3-acetyl-2,3,4,'5- tetrahydro-lH-3-benzazepine (m.p. 60-63C) were added in small portions over a period of minutes to 588 gm (5.06 mols) of chlorosulfonic acid at 5C, and the mixture was stirred for 4 hours at 5 to 0C. Thereafter, the solution was poured over ice, and the aqueous mixture was extracted with benzene. The benzene extract was dried and evaporated, leaving 164 gm of raw 3-acetyl-2,3,4,5-tetrahydro-1H-3- benzazepine-7-sulfochloride as a viscous oil.

b. The raw sulfochloride obtained in (a) was added to 400 ml of concentrated ammonia, the mixture was gently heated on a water bath, whereby a clear solution was quickly formed, and the solution was allowed to cool. 84.7 gm of colorless 3-acetyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-sulfonamide, m.p. 177-180C, precipitated out. Upon extraction of the mother liquor with ethylacetate and evaporation of the extract solution, an additional 7.6 gm of the product (m.p. l76-l 8 0C) were recovered.

CalculatedzC 53.72%;1-1 6.01%;N 10.44%

Found:C 53.50%;1-1 6.10%;N 10.20%

c. All of the 92.3 gm of sulfonamide obtained in (b) were admixed with 1 liter of semi-concentrated hydrochloric acid, and the mixture was refluxed for 15 hours. Thereafter, the acidic solution was evaporated to dryness, the residue was treated several times with boiling ethanol, i.e., by adding ethanol and boiling the alcohol off again, and then one equivalent of 1 N sodium hydroxide was added. The alkaline mixture as heated, stirred and allowed to cool, yielding 72.8 gm of raw crystallizate, m.p. 218-220C. The raw product was recrystallized from 2 liters of aqueous ethanol, yielding 472 gm of colorless 2,3,4,5-tetrahydro-lH-3- benzazepine-7-sulfonamide, m.p. 225-228C, of the formula AnalysiszC l-l N O S;mol. wt. 226.3

Calculated:C 53.07%;H 6.25%;N 12.37%

Found:C 52.50%;H 6.17%;N 12.24%

The following table lists additional sulfonamide starting compounds of the formula II which were prepared in analogy to Examples C, D, I, .l or K above.

TABLE (CI I2)n Prepared analogous to R 11 A M.P. Example p-F1uoropheny1 1 CH 165169 C D p-Ch1oropheny1- 1 CH- 147-150 C. J

p-Bromopheny1 1 CH- 146-148 C I m,p-Dich1oropheny1- 1 CH- 200202 C. 1)

p-Methylphenyl- 1 -CII 165168 C I) p-Trifiuoromethylphenyl- 1 -CII- Viscous oil D p-Ethoxyphenyl 1 CH Foam D p-n-1rop0Xyphcny1- 1 GII do D jlh p-Diphenyl- 1 0H 188-192 1) a-Naphthy1 1 CH 203-207 C D p-Chlorophenyl 2 -CH Foam K pBromophe11y1- 1. 2 CH do K n-Propyl $21331 11:: m-Tolylp-To1y1 o-Methoxyphenylp-Methoxyphenylm-Trifluoromethylphenyl. Naphthyl-(l) 1,2,3,4-tetrahydronaphthy1(1) Indany1 (1) Pheny1 I CH1 Benzoyll -C II:

1 -CII1-CII2 Ph0ny1 I (III; -01];- 4-nmthy1ph0nyll (JH -(,lI,- p-Chl0r0phcnyl 1. 4 l -(JH -CH 111-ChI0r0pI10ny1 1 ()ll (3II,- p-Trifiuoromethylph 1yl 1 CI[;-CH p-Methoxyphenyl 1 CH CII o-Methoxypheny1 1 CHz 01-12- Phenyl- 1 CH OH D0 1 CII CI'I2" 164-166 C 0 D0 1 CHCH2- Solidfnam I) Do 1 --OIIC1I 130-134 I) Do 1 -CHCI I1 164169 C C TABLE Continued Prepared analogous to R; n A 11.1. Example Do 1 -]CH--CH 246-250" C C D 1 -CHr-CHzCHz-.. Mil-146 C C From benzoyl ethyl acetate and 1, 2, 3, 4-tetrahydro-isoqulnoline-7-sulfonamide in xylene.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

EXAMPLE 1 Preparation of l ,2,3 ,4-Tetrahydro-2-( 3 'phenylpropionyl)-7-(N'-cyclohexyl-ureido-N-sulfonylisoquinoline by method A 41.4 gm (0.12 mol) of 2-(3'-phenyl-propionyl)- l,2,3,4-tetrahydro-isoquinoline-7-sulfonamide (rn.p. 222227C) were admixed with an equirnolar amount of l N sodium hydroxide (120 ml) and 200 ml of ethanol, the solution was evaporated to dryness in vacuo, and the residue was dried for 30 minutes at 80C in a vacuum of 12 mm Hg, yielding the sodium salt of 2- 3 -phenyl-propionyl 1 ,2,3 ,4-tetrahydro-isoquinoline- 7-sulfonamide. This sodium salt was suspended in 1 liter of nitrobenzene, and 15.05 gm (0.12 mol) of cyclohexyl isocyanate were added dropwise to the suspension. The mixture was stirred for hours at 95C and then cooled, the precipitate formed thereby was centrifuged off and dissolved in hot water, the hot aqueous solution was allowed to cool, extracted with ether and poured into a mixture consisting of ice and an excess of concentrated hydrochloric acid. The precipitate formed thereby was collected by vacuum filtration, washed with a large amount of water, thoroughly air-dried by suction and taken up in ethanol. The ethanolic solution was evaporated in vacuo, the residue was taken up in hot ethylacetate, the resulting solution was dried over sodium sulfate and filtered, and the filtrate was concentrated by evaporation to the point where the solution just stayed clear at the boiling point. Upon cooling thereof, 31.5 gm of 1,2,3,4- tetrahydro-2-( 3 '-phenyl-pr0pionyl )-7-( N -cycl0hexylureido-N-sulfonyl)-isoquinoline, m.p. f 135-140c (thin-layer chromatogram single spot), of the formula crystallized out.

AnalysiszC- H N 0., S;mol. wt. 469.6

Calculated:C 63.95%;H 6.65%;N 8.95% FoundzC 64.00%;H 6.55%;N 9.02%

EXAMPLE 2.

EXAMPLE 3 Using a procedure analogous to that described in Example 1 l,2,3,4-tetrahydro2-acetyl-7-(N-cyclohexylureido-N-sulfonyl)-isoquinoline, m. p. -llOC.

(acid precipitation), of the formula was prepared from 1 1.1 gm of 2-acetyl- 1 ,2,3 ,4- tetrahydroisoquinoline-7- sulfonamide (m. p. 220224 C.) and 5.46 gm of cyclohexylisocyanate. The yield was 8.4 gm.

AnalysiszC H N 0., S;mol. wt. 379.4

Calculated:C 56.98%;H 6.64%;N 1 1.07%

Found:C 56.80%;1-1 6.71%;N 10.70%

EXAMPLE 4 Using a procedure analogous to that described in Example 1, 1,2,3,4-tetrahydro-2-benzoyl-7-(N'-cyclohexylureido-N-sulfonyl)-isoquinoline, m. p. 155C.

(from methyl ethyl ketone of the formula was prepared from 18.0 gm of 2-benzoyl-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide, (m. p. 222224 C.) and 7.15 gm of cyclohexyl isocyanate. The yield 5 was 10.4 gm.

Analysis:C, H N 0 S;mol. wt. 441.5

Calculated:C 62.57%;H 6.16%;N 9.52% Found:C 62.60%;H 6.12%;N 9.31%

EXAMPLE Using a procedure analogous to that described in Example 1, 1 ,2,3,4-tetrahydro-2-(3 '-methyl-benzoyl)-7- (N'-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 154- 158C. (after column-chromatography and stirring with ether), of the formula was prepared from 19.8 gm of 2-(3-methyl-benzoyl)- 1,2,3,4-tetrahydro-isoquinoline-7-sulfonamide, (m. p. 240247C.) and 7.5 gm of cyclohexyl isocyanate. The yield was 5.2 gm. AnalysiszC H N 0 S;mol. wt. 455.6

Calculated:C 63.30%;H 6.42%;N 9.22% Found:C 63.00%;H 6.27%;N 8.79%

EXAMPLE 6 Using a procedure analogous to that described in Example 1, 1,2,3,4-tetrahydro-2-(4'-methyl-benzoyl)7- (N"cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 130-135C. (after column-chromatography and stirring with ether), was prepared from 21.4 gm of 2-(4- methyl-benzoyl)-1,2,3 ,4-tetrahydro-isoquinoline-7-sulfonamide, (m. p. 230235C.) and 8.14 gm of cyclohexyl isocyanate. The yield was 6.2 gm. AnalysiszC H N 0 S;mol. wt. 455.6

Calculated:C 63.30%;H 6.42%;N 9.22%

Found:C 63.00%;H 6.40%;N 8.79%

EXAMPLE 7 Using a procedure analogous to that described in Example l, 1,2,3,4-tetrahydro-2-(2'-methyl-3-phenyl propionyl)-7-(N'-cyclohexyl-ureido-N-sulfonyl)- isoquinoline, m. p. 1041 C. (acid precipitation), of the formula was prepared from 14.34 gm of 2-(2'-methyl-3'-phenylpropionyl)- l ,2,3 ,4-tetrahydro-isoquinoline-7-sulfonamide, (m. p. 214-215C.) and 5.01 gm of cyclohexyl isocyanate. The yield was 9.8 gm. AnalysiszC, H N 0 S;mol. wt. 483.7.

Calculated:C 64.58%;H 6.88%;N 8.69% Found:C 64.50%;H 6.93%;N 8.72%

EXAMPLE 8 Using a procedure analogous to that described in Example 1, l,2,3,4-tetrahydro-2-(a-naphthoyl)-7-(N- cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 170l75C. (after column-chromatography and stirring with acetone), of the formula was prepared from 18.3 gm of 2-( a-naphthoyl)-l ,2,3,4- tetrahydro-isoquinoline-7-sulfonamide, (m. p. 24024 5C.) and 6.3 gm of cyclohexyl isocyanate. The yield was 4.5 gm. AnalysiszC H N 0 S;mol. wt. 491.6

Calculated:C 66.00%;H 5.95%;N 8.55% FoundzC 65.90%;H 5.85%;N 8.74%

EXAMPLE 9 Using a procedure analogous to that described in Example 1, 1,2,3,4-tetrahydro-2-(2-methoxy-benzoyl)-7- (N-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. -150C. (from ethanol), of the formula was prepared from 13.9 gm of 2-(2'methoxy-benzoyl)- 1,2,3,4-tetrahydro-isoquinoline-7-sulfonamide, (m. p. 232238C.) and 5.02 gm of cyclohexyl isocyanate. The yield was 9.5 gm. Analysis:C, H N O S;mol. wt. 471.6

Calculated:C 61.14%;1-1 6.20%;N 8.91% FoundzC 60.60%;1-1 6.18%;N 9.09%

EXAMPLE 10 EXAMPLE 11 Using a procedure analogous to that described in Example 1, l,2,3,4-tetrahydro-2-phenylacetyl-7-(N'- cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. l40145C. (after stirring with ethylacetate and ether), of the formula was prepared from 5.57 gm of 2-phenylacetyl-l,2,3,4- tetrahydro-isoquinoline-7-sulfonamide, (m. p. 182-18 7C.) and 2.12 gm of cyclohexyl isocyanate. The yield was 5.0 gm. AnalysiszC H N 0 S;mol. wt. 455.6

Calculated:C 63.28%;1-1 6.42%;N 9.22% Found:C 63.00%;1-1 6.52%;N 9.14%

EXAMPLE 12 Using a procedure analogous to that described in Example l, l,2,3,4-tetrahydro-2-(3,3'-diphenyl-propionyl)-7-(N-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 17 l-l 74C. (reprecipitated from acetone with water), of the formula was prepared from 12.6 gm of 2-(3,3-diphenylpropionyl)-1 ,2,3 ,4-tetrahydro-isocluinoline-7-sulfonamide, (m. p. 246250C.) and 3.80 gm of cyclohexyl isocyanate. The yield was 9.55 gm. AnalysiszC H N S;mol. wt. 545.7

Calculated:C 68.23%;H 6.46%;N 7.70% Found:C 68.20%;H 6.34%;N 7.65%

EXAMPLE 13 Using a procedure analogous to that described in Example 1, l,2,3,4-tetrahydro-2-(4-phenyl-butyry1)-7- (N'-cyclohexyl-ureido-N-sufonyl)-isoquinoline, m. p. 7785C. (recrystallized from ether with petroleum ether), of the formula was prepared from 7.17 gm of 2-(4'-phenyl-butyryl)- 1,2,3,4-tetrahydro-isoquino1ine-7-sulfonamide, (m. p. 140-146C.) and 2.51 gm of cyclohexyl isocyanate. The yield was 2.7 gm. Analysis:C H N 0 S;mol. wt. 483.7

Calculated:C 64.58%;1-1 6.88%;N 8.69% Found:C 64.80%;1-1 6.79%;N 8.39%

EXAMPLE 14 Using a procedure analogous to that described in Example l, l,2,3,4-tetrahydro-2-(3'-benzoyl-propionyl)- 7-(N'-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 183184C. (from acetone), of the formula was prepared from 3.37 gm of 2-(3'-benzoyl-propionyl)-1 ,2,3 ,4-tetrahydro-isoquinoline-7-sulfonamide, (m. p. 187-189C.) and 1.14 gm of cyclohexyl isocyanate. The yield was 3.7 gm. AnalysiszC H N O S;mol. wt. 497.7

Calculated:C 62.77%;1-1 6.28%;N 8.45% Found:C 62.50%;1-1 6.20%;N 8.26%

EXAMPLE 15 Using a procedure analogous to that described in Example 1, 1,2,3,4-tetrahydro-2-(3-p-tolyl-propionyl)-7- (N'-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 134-136C. (from ethyl acetate), of the formula EXAMPLE 16 Using a procedure analogous to that described in Example 1, 1,2,3,4-tetrahydro-2-[3-(ptrifluoromethylphenyl)-propionyl]-7-(N'-cyclohexylureido-N-sulfonyl)-isoquino1ine, m. p. 130-133C.

15 (from ethyl acetate), of the formula was prepared from 3.10 gm of 2-[3"(ptrifluoromethyl-phenyl)-propionyl]-1,2,3 ,4- tetrahydro-isoquinoline-7-sulfonamide, (m. p. l8418 6C.) and 0.95 gm of cyclohexyl isocyanate.

The yield was 1.7 gm.

AnalysiszC H F 'N O S;mo1. wt. 537.6

' Calculated:C 58.09%;H 5.63%;N 7.82%

Found:C 58.10%;H 5.80%;N 7.81%

' EXAMPLE 17 Using a procedure analogous to that described in Example 1, 1 ,2,3,4-tetrahydro-2-[3 '-(o-methoxy-phen yl)- propionyl]-7-(N'-cyclohexyl-ureido-N-sulfonyl)- isoquinoline, m. p. 194196C. (dec0mp.; from ethanol), was prepared from 11.2 gm of 2-[3'-(omethoxy-phenyl )-propionyl]-1 ,2,3 ,4-tetrahydroisoquinoline-7-sulfonamide, (m. p. 232238C.) and 3.76 gm of cyclohexyl isocyanate. The yield was 11.1

Analysis:C H N 0,, S;mol. wt. 499.6

Calculated:C 62.51%;H 6.66%;N 8.41 Found:C 62.50%;H 6.75%;N 8.45%

EXAMPLE 18 Using a procedure analogous to that described in Example 1, l,2,3,4-tetrahydro-2-(2'-phenyl-butyryl)-7- (N'-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 18l-185C. (from ethanol), of the formula mu {34111241112 S02 N NH EXAMPLE 19 Sodium salt of 1,2,3,4-tetrahydro-2-[3'-(mchlorophenyl)-propionyl]-7-(N-cyclohexyl-ureido-N- sulfonyl )-isoquinoline A mixture consisting of 1 1.4gm (0.03 mol) of 2-(3- m-chlorophenyl-propionyl )-l ,2,3,4-tetrahydroisoquinoline-7-sulfonamide (m. p. 172-174C.), a solution of 1.68 gm (0.03 mol) of potassium hydroxide in 20 ml of water, and 100 ml of ethanol was evaporated to dryness in vacuo. The dry potassium salt of the sulfonamide thus obtained was added to 300 ml of nitrobenzene, 3.76 gm (0.03 mol) of cyclohexyl isocyanate were added dropwise thereto, and then the reaction mixture was stirred for 5 hours at 100C. Thereafter, the nitrobenzene was removed by steam distillation, the residue was dissolved in hot water, and the hot aqueous solution was filtered through a G3-frit into an agitated mixture of ice and excess concentrated hydrochloric acid. The precipitate formed thereby was taken up in hot ethanol, the solution was treated with activated charcoal and then filtered, and the hot filtrate was admixed with a solution of one equivalent of sodium hydroxide in the minimum required amount of water. Upon cooling, 6.5 gm of the sodium salt of 1 ,2 ,3 ,4-tetrahydro-2- 3 m-chlorophenyl )-propionyl] -7-(N-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, which decomposed beginning at 280C, crystallized out. AnalysiszC H N3 0., S Na;mol. wt. 526.1

Calculated:C 57.08%;H 5.56%;N 7.99%

Found:C 57.30%;H 5.67%;N 7.80%

EXAMPLE 20 Sodium salt of 2-( 3 '-phenyl-butyryl)-1,2,3 ,4- tetrahydro-7-(N'-cyclohexyl-ureido-N-sulfonyl)- isoquinoline A mixture consisting of 12.53 gm (0.035 mol) of 2- (3 -phenyl-butyryl )-1 ,2,3 ,4-tetrahydro-isoquinoline (m. p. 164166C.), 35 ml of 1N sodium hydroxide and 100 ml of ethanol was evaporated to dryness in vacuo. The dry sodium salt of the sulfonamide thus obtained was suspended in 300 ml of nitrobenzene, and 4.38 gm (0.035 mol) of cyclohexyl isocyanate were added dropwise to the suspension. Thereafter, the mixture was stirred for 5 hours at 100C, and then the precipitate which had formed was separated by centrifuging and dissolved in hot water. The aqueous solution was allowed to cool, was then extracted with ether, thereafter heated again, and finally filtered through a G3-frit into an agitated mixture of ice and excess concentrated hydrochloric acid. The precipitate formed thereby was collected by vacuum filtration and dissolved in hot ethanol, and then a solution of 0.035 mol of sodium hydroxide in the minimum required amount of water was added to the ethanolic solution. Upon cooling, 8.3 gm of the colorless sodium salt of 2-(3- phenyl-butyryl l ,2,3 ,4-tetrahydro-7-(N -cyc1ohexylureido-N-sulfonyl)isoquinoline, m. p. 280285C. (decomp.) crystallized out. Analysis:C l-l N 0 S Na;mol. wt. 505.6

Calculated:C 61.72%;1-1 6.38%;N 8.30%

Found:C 61.40%;1-1 6.42%;N 8.30%

EXAMPLE 21 Using a procedure analogous to that described in Example 20, the sodium salt of 1,2,3,4-tetrahydro-2-butyryl-7-(N'-cyc1ohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 300C. (from ethanol), was prepared from 8.46 gm of 2-butyryl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonamide (m. p. l59-162C.) and 3.76 gm of cyclohexyl isocyanate. The yield was 10.0 gm. AnalysiszC H N 0 S Na;mol. wt. 429.5

Calculated:C 55.93%;1-1 6.57%;N 9.78%

Found:C 55.60%;1-1 6.68%;N 9.66%

EXAMPLE 22 Using a procedure analogous to that described in Example 20, the sodium salt of 1,2,3,4-tetrahydro-2-(3'- phenyl-propionyl)-7-(N'-n-butyl-ureido-N-sulfonyl)- isoquinoline, m. p. 244245C. (decomp.; from ethanol), of the formula was prepared from 10.3 gm of 2-( 3'-pheny1-propionyl)- 1,2,3,4-tetrahydro-isoquinoline-7-sulfonamide (m. p.

222-227C.) and 2.98 gm of n-butyl-isocyanate. The

yield was 10.1 gm.

AnalysiszC 1-1 N, 0. S Na;mol. wt. 465.6 I Calculated:C 59.35%;1-1 6.06%;N 9.02% FoundzC 59.20%;H 6.24%;N 8.92%

EXAMPLE 23 Using a procedure analogous to that described in Example 20, the sodium salt of l,2,3,4-tetrahydro-2-(3- p-methoxyphenyl-propionyl)-7-(N-cyclohexyl-ureido- N-sulfonyl)-isoquinoline, m. p. 255C. (decomp.; from ethanol), was prepared from 6.75 gm of 2-(3 pmethoxyphenyl-propionyl l ,2,3 ,4-tetrahydro-isoquinoline-7-sulfonamide (m. p. l66167C.) and 2.26 gm of cyclohexyl isocyanate. The yield was 6.8 gm. AnalysiszC H N 0 S Na;mol. wt. 521.6

Calculated:C 59.87%;1-1 6.18%;N 8.06%

Found:C 59.70%;H 6.37%;N 8.05%

EXAMPLE 24 Using a procedure analogous to that described in Example 20, the sodium salt of 1 ,2,3,4-tetrahydro-2-(3'- phenyl-hexanoyl )-7-( N '-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 255260C. (from methanol), of the formula A EXAMPLE 28 .1.

. Y ample 20, the sodium salt of l,2,3,4-tetrahydro-2- isovaleroyl-7-(N'-cyclohexyl-ureido-N-sulfonyl)- JII2 N1I( -N1I 1r -Na isoquinoline, m. p. 290C. (decomp; from ethanol), (3H was prepared from 10.4 gm' of 2-(isovaleroyl-l,2,3,4-

tetrahydro-isoquinoline-7-sulfonamide (m. p. 14214 was prepared from 11.6 gm of 2-(3'-phenyl-hexanoyl)- 5C.) and 4.38 gm of cyclohexyl isocyanate. The yield 1,2,3,4-tetrahydro-isoquinoline-7-su1fonamide (m. p. 10 8 130134C.) and 3.76 gm of cyclohexyl isocyanate. AnalyslsiczlHim a O4SNamoL 443-6 The yield was 5.65 gm. CalculatedzC 56.87%;H 6.82%;N '9.47%

Analysis:C H N 0,, S Na;mol. wt. 533.7 Fmmdlc 930% Calculated:C 63.00%;1-1 6.81%;N 7.88% Found:C 63.30%;1-1 7.05%;N 7.59% EXAMPLE 29 Using a procedure analogous to that described in Ex- EXAMPLE 25 ample 20, the sodium salt of 1,2,3,4-tetrahydro-2-(3- Using a procedure analogous to that described in Extrifluoromethyl-benzoyl)-7-(N-cyclohexyl-ureido-N- ample 20, the sodium salt of 1,2,3,4-tetrahydro-2-(3'- sulfonyl)-isoquinoline, m. p. 280-285C. (decomp.; phenyl-propionyl)-7-[N'-adamantyl-( l )-ureido-N-sulfonyl]-isoquinoline, m. p. 260C. (decomp; from 2-(31,2,3,4-tetrahydroacetone by addition of water), of the formula isoquinoline-7-sulfo'namide (m. p. 250-255C.) and I O l 0 I612 l CHHPCHPOHPLN sOZNH-6NHG CH-Na CH2 CH1 HzC (3H2 CH2 was pre ared from 6.22gm of 2-(3'-phen l-pro ionyl)- 3.73 gm of cyclohexyl isocyanate. The yield was 1.65

P y P 3 5 1,2;3,4-tetrahydro-isoquinoline-7-sulfonamide (m. p. gm. 222-227C.) and 3.20 gm of adamantyl-( 1) isoy zl 3 a 4 S 531-6 cyanate. The yield was 1.08 gm. Calculated:C 54.23%;H 4.76%;N 7.91% Analysis:C H N 0 S Na;mol. wt. 543.7 Found:C 53.90%;1-1 5.02%;N 7.70%

CalculatedzC 64.06%'H 6.30%'N 7.73%

1 i i 40 Found:C 64.20%;H 6.60%;N 7.57% EXAMPLE Using a procedure analogous to that described in Ex- EXAMPLE 26 ample 20, the sodium salt of l,2,3,4-tetrahydro-2- Using a procedure analogous to that described in Exbenzoylacetyl-7-(N'-cyclohexyl-ureido-N-sulfonyl)- ample 20, the sodium salt of l,2,3,4-tetrahydro-2-(3'- isoquinoline, m. p. 230-231C. (decomp.; after henyI-vaIer DJ-(N'- cloh leid N- ]f column-chromatography and recrystallization from Using a procedure analogous to that described in Exfrom ethanol and ether), was prepared from 11.4 gm of v nyl)-isoquinoline, m. p. 272280C. (decomp.; from methanol), was P p from gm 0f ethanol), was prepared from 13.6 gm of 2-(3'-ph 1- benzoylacetyl-l,2,3,4-tetrahyd ro-isoquinoline-7-sulvaleroyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonafonamlde P- 151 453 and g of mide and 5.0 gm of cyclohexyl isocyanate. The yield y y y The yield was 05 AnalyslszC H N 0 S Na;mol. wt. 505.6

was 7.65 gm.

Analysiszcwl H34 N3 0 S L wt 5195 Calculated:C 59.39%;H 5.58%;N 8.31%

Calculated:C 62.40%;1-1 6.60%;N 8.10% F0und=C 14% FoundzC 62.20%;H 6.73%;N 8.00% EXAMPLE 3] EXAMPLE 27 Using a procedure analogous to that described in Ex- Using a procedure analogous to that described in Example 20, the Sodium Salt of y ample 20, the sodium salt of 1,2,3,4-tetrahydro-2-(3- hy p y y 1- p-chlorophenyl-propionyl)-7-(N-cyclohexyl-ureido- 0 f lg' y T-" P- N-sult'onyl)-isoquinoline, m. p. 260-263C. (decomp.; 268 (decomu; from ethanol). Ofthe formula from ethanol), was prepared from 4.55 gm of 2-(3'-pchlorophenyl-propionyl)-l ,2,3,4-tetrahydro-isoquin- Q 0 A oline-7-sulfonamide (m. p. 15516lC.) and 1.5 gm of IL l cyclohexyl isocyanate. The yield was 3.5 gm. AnalysiszC H Cl N 0 S Na;mol. wt. 526.1

0 Calculated:C 57.08%;1-1 5.56%;N 7.99% Ll H Na F0und:C 56.90%;H 5.63%;N 7.80% v EXAMPLE 32 Using a procedure analogous to that described in Example 20, the sodium salt of 1,2,3,4-tetrahydro-2-[3'- (5 "-chloro-2 -methoxy-phenyl)-propionyl]-7-(N'- cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. 270C. (decomp.; from ethanol), of the formula was prepared from 20.4 gm of 2-[3'-(5"-chloro-2"- methoxyphenyl)-propionyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 6.26 gm of cyclohexyl isocyanate. The yield was 1 1.5 gm.

AnalysiszC H Cl N 0 S Na;mol. wt. 556.1

Calculated:C 56.16%;H 5.62%;N 7.56% FoundzC 55.95%;H 5.62%;N 7.30%

EXAMPLE 33 Using a procedure analogous to that described in Example 20, the sodium salt of 1,2,3,4-tetrahydro-2-[indanyl-( l )-acetyl]-7-( N-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 273276C. (decomp.; from isopropanol/water), of the formula was prepared from 11.1 gm of 2-[indanyl-(1)-acetyl]- l,2,3,4-tetrahydro-isoquinoline-7-sulfonamide (m. p.

160165C., decomp.) and 3.76 gm of cyclohexyl isocyanate. The yield was 6.4 gm.

Analysis:C H N 0 S Na;mol. wt. 517.6

Calculated:C 62.65%;H 6.23%;N 8.12% Found:C 63.00%;1-1 6.04%;N 8.35%

EXAMPLE 34 EXAMPLE 35 Using a procedure analogous to that described in Example 20, the sodium salt of l,2,3,4-tetrahydro-2-(2- p-fluorophenyl-propionyl)-7-(N'-cycl0hexyl-ureido-N- sulfonyl)-isoquinoline, m. p. 2l8223C. (decomp.; from ethanol), was prepared from 3.99 gm of 2-(2-pfluorophenyl-propionyl)- l ,2,3,4-tetrahydro-isoquinoline-7-sulfonamide (m. p. l65-169C.( and 1.52 gm of cyclohexyl isocyanate. The yield was 2.6 gm. AnalysiszC H F N 0 S Na;mol. wt. 509.6

Calculated:C 58.93%;H 5.74%;N 8.25%

Found:C 58.60%;1-1 6.05%;N 8.40%

EXAMPLE 36 Using a procedure analogous to that described in Example 20, the colorless sodium salt of 1,2,3,4- tetrahydro-2-(3,4'-dichlorophenyl-propionyl)-7-(N'- cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 238240C. (decomp.; from methanol/benzene), was prepared from 4.8 gm of 2-(3',4'-dichlorophenylpropionyl)-1,2,3 ,4-tetrahydro-isoquinoline-7-sulfonamide (m. p. 200-202C.) and 1.59 gm of cyclohexyl isocyanate. The yield was 2.47 gm.

Analysis:C H C1 N 0 S Na;mol. wt. 560.5

Calculated:C 53.61%;H 5.01%;N 7.50%

FoundzC 53.60%;1-1 5.13%;N 7.43%

EXAMPLE 37 Using a procedure analogous to that described in Ex ample 20, except that the reaction mixture was centrifuged after addition of cyclohexane and the separated solids were recrystallized right away from ethanol/methanol, the colorless sodium salt of l,2,3,4- tetrahydro-2-(2'-p-tolyl-propionyl)-7-(N'-cyclohexylureido-N-sulfonyl)-isoquinoline, m. p. 233235C., was prepared from 8.1 gm of 2-(2-p-tolyl-propionyl)- 1,2,3,4-tetrahydro-isoquinoline-7-sulfonamide (m. p. l65-l68C.) and 3.10 gm of cyclohexyl isocyanate. The yield was 6.5 gm. Analysis:C H N 0., S Na;m0l. wt. 505.6

Calculated:C 61.72%;H 6.39%;N 8.32% Found:C 61.70%;1-1 6.65%;N 8.57%

EXAMPLE 38 2-(2'-p-Trifluoromethylphenyl-propionyl)-1,2,3 ,4- tetrahydro-7-(N'-cyclohexyl-ureido-N-sulfonyl)- isoquinoline and its sodium salt 6.5 gm of viscous 2-(2'-p-trifluoromethylphenylpropionyl l ,2,3 ,4-tetrahydro-isoquinoline-7-sulfonamide were reacted with 2.17 gm of cyclohexylisocyanate, analogous to Example 20, and the precipitate was centrifuged off. The solid product obtained thereby was extracted with 2N hydrochloric acid and chloroform, the chloroform extract solution was evaporated, and the residue was purified by columnchromatography on silicagel (solvent system cyclohexane acetone glacial acetic acid l0:5:0.1). 2.4 gm of foam-like 2-(2-p-trifluoromethylphenyl-propionyl)- 1 ,2,3 ,4-tetrahydro-7-(N -cyclohexyl-ureido-N-sulfonyl)-isoquino1ine were obtained, which were then converted into the sodium salt, m. p. 224-227C. (decomp.; from ethanol and a little benzene) as described in Example 20. AnalysiszC H F N 0 S Na;mol. wt. 559.6

Calculated:C 55.85%;H 5.23%;N 7.52%

Found:C 56.10%;H 5.17%;N 7.64%

EXAMPLE 39 2-(2'-p-Ethoxyphenyl-propionyl)-1,2,3 ,4-tetrahydro- 7-(N'-cyclohexyl-ureido-N-sulfonyl)-isoquinoline and its sodium salt 135 gm of foamy 2-(2-p-ethoxyphenyl-propionyl)- l ,2,3,4rtetrahydro-isoquinoline-7-sulfonamide were reacted with 1.77 gm of cyclohexyl isocyanate analogous to Example 20. After completion of the reaction, three to four times the volume of absolute ether was added to the reaction solution, and the light yellow precipitate formed thereby was collected by vacuumfiltration and recrystallized from ethanol in the presence of activated charcoal, yielding 6.0 gm of the raw sodium salt of 2-(2'-p-ethoxyphenyl-propionyl)- 1,2,3 ,4-tetrahydro-7-(N '-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 220-224C. For purification, the raw salt was taken up in 2N HC1 and chloroform, the chloroform phase was evaporated, and the residue (5.7 gm) was chromatographed as described in Example 38, yielding the colorless, foamy free 2-acyl-7- ureidosulfonyl-tetrahydroisoquinoline which was then again converted into its sodium salt, m. p. 224226C. The yield of salt was 1.18 gm. AnalysiszC H N S Na;mol. wt. 535.6

CalculatedzC 60.55%;H 6.40%;N 7.85%

Found:C 60.75%;H 6.50%;N 7.80%

EXAMPLE 40 Using a procedure analogous to that described in Example 39, 1,2,3,4-tetrahydro-2-(2'-p-n-propoxyphenyl-propionyl)-7-(N'-cyclohexyl-ureido-N-sulfonyl)- isoquinoline, m. p. 122-124C. (from acetone/ether), was prepared from 13.5 gm of foamy 2-(2'-p-n-propoxyphenyl-propionyl)-l ,2,3 ,4-tetrahydro-isoquinoline-7- sulfonamide and 4.62 gm of cyclohexyl isocyanate. AnalysiszC H N 0 S;mol. wt. 527.6

Calculated:C 63.65%;H 7.08%;N 7.96%

Found:C 63.45%;H 6.88%;N 8.01%

Its sodium salt had a melting point of 232234C.

AnalysiszC H N 0 S Na;mol. wt. 549.6

Calculated:C 61 .20%;H 6.61%;N 7.65% Found:C 61 .25%;H 6.78%;N 7.88%

EXAMPLE 41 Using a procedure analogous to that described in Example 39, the sodium salt of 1,2,3,4 tetrahydro-2-(2'- p-diphenyl-propionyl)-7-(N'-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 245250C. (decomp.), was prepared from 6.6 gm of 2-(2'-p-diphenyl)-l,2,3,4- tetrahydro-isoquinoline-7-sulfonamide (m. p. l8819 2C.) and 2.16 gm of cyclohexyl isocyanate. The yield was 1.5 gm.

AnalysiszC H N 0 S Na;mol. wt. 567.7

Calculated:C 65.57%;H e 6.04%;N 7.41%

Found:C 65.30%;1-1 6.16%;N 7.50%

EXAMPLE 42 Using a procedure analogous to that described in Example 37, the colorless sodium salt of 1,2,11,4- tetrahydro-2-[2'-(a-napthyl)-propionyl]-7-(N'- cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p, 263265C. (decomp.; from ethanol/benzene), was prepared from 2.65 gm of 2-[2'-(a-naphthyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-7-sulfonamide (m. p. 203-207C.) and 0.93 gm of cyclohexyl isocyanate. The yield was 0.65 gm.

Analysis2C H N 0,, S Na;mol. wt. 541.6

Calculated:C 64.31%;1-1 5.95%;N 7.76% Found:C 64.20%;1-1 6.02%;N 7.90%

EXAMPLE 43 2,3,4,5-Tetrahydro-3-(2'-p-bromophenyl-propionyl)- 7-(N'-cyclohexyl-ureido-N-sulfonyl)-111-3- benzazepine 8.7 gm of foamy 3-(2-p-bromophenyl-propionyl)- 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide and 2.74 gm of cyclohexyl isocyanate were reacted analogous to Example 20. After completion of the reaction, absolute ether was added to the reaction solution, and the yellowish precipitate formed thereby was taken up in 2N HCl and chloroform. The chloroform phase was evaporated, the residue was purified by column-chromatography on silicagel (solvent system cyclohexane acetone glacial acetic acid 30: 10:0.2) and the colorless, foamy product was crystallized by triturating it with acgtonqmethyl ethyl ketone, yielding 2 ,3 ,4,5 -tetrahydro 3 (2' -p-bromophenyl propionyb- 7-(N -cyclohexylureido-Nsulfonyl)- 1 H-3 benzazeine, m. p. 208-210C. (decomp.), of the formula Analysis: C H Br N 0 S; mol. wt. 562.5

Calculated: C 55.55%; H 5.74%; N 7.48% Found: C 55.50%; H 5 5.63%; N 7.38%

EXAMPLE 44 Using a procedure analogous to that described in Example 43, crystalline 2,3,4,5-tetrahydro-3-(2'-pchlorophenyl-propionyl)-7-(N-cyclohexyl-ureido-N- sulfonyl)-1H-3-benzazepine, m. p. 205-207C., was prepared from 1.8 gm of foamy 3-(2-p-chlorophenylpropionyl )-2 ,3 ,4,5-tetrahydrol l-l-3-benzazepine-7- sulfonamide and 0.63 gm of cyclohexyl isocyanate. Analysis: C H C1N 0 S; mol. wt. 518.1

Calculated: C 60.27%; H 6.23%; N 8.11%

Found: C 60.10%; H 6.16%; N 7.93%

EXAMPLE 45 insoluble matter was collected by vacuum filtration,

air-dried and recrystallized from ethylacetate. 1.5 gm of 1 ,2,3,4-tetrahydro-2-(3 -phenyl-propionyl)-7-[N- (4-methyl-cyclohexyl)-ureido-N-sulfonyl]-isoquinoline, m. p. 155-158C., ofthe formula lil EXAMPLE 46 Sodium salt of 2-(3'-phenyl-propionyl)-1,2,3,4- tetrahydro-7-(N-cycloheptyl-ureido-N-sulfonyl)- isoquinoline A mixture consisting of 4.17 gm (l millimols) of N- [2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-7sulfonyl]-carbamic acid ethyl ester (m. p. 138141C.), 1.25 gm (ll millimols) of cycloheptylamine and ml of anhydrous dimethylformamide was heated for 1 hour at 100C. and then for 30 minutes at 130C. Thereafter, the reaction solution was evaporated in vacuo, the residue was taken up in hot ethanol in the presence of activated charcoal, the mixture was filtered, the filtrate was admixed with a solution of one equivalent of sodium hydroxide in the minimum required amount of water, and the mixed solution was cooled. 3.3 gm of the sodium salt of 2-(3'- phenyl-propionyl)-l ,2,3 ,4-tetrahydro-7-(N'cycloheptyl-ureido-N-sulfonyl)-isoquinoline, m. p. 268270C. (decomp.), crystallized out. Analysis: C H N 0 S Na; mol. wt. 505.6

Calculated: C 61.72%; H 6.38%; N 8.30%

Found: C 61.80%; H 6.59%; N 8.10%

EXAMPLE 47 Using a procedure analogous to that described in Example 46, 3.8 gm of the sodium salt of 2-(3-phenylpropionyl)-l ,2,3,4-tetrahydro-7-(N-cyclooctylureido-N-sulfonyl)-isoquinoline, m. p. 270275C. (from ethanol), were obtained from 4.17 gm of N-[2-(3 '-phenyl-propionyl)-1,2,3 ,4-tetrahydroisoquinoline-7- sulfonyl]-carbamic acid ethyl ester (m. p. 138141 C.) and 1.40 gm of cyclooctylamine.

Analysis: C H N 0 S Na; mol. wt. 519.7

Calculated: C 62.41%; H 6.60%; N 8.09%

Found: C 62.10%; H 6.45%; N 7.89%

EXAMPLE 48 Using a procedure analogous to that described in Example 46, 3.0 gm of the sodium salt of 2-(3'-phenylpropionyl)-1,2,3,4-tetrahydro-7-(N '-cyclopentylureido-N-sulfonyl)-isoquinoline, m. p. 260262C. (decomp.; from ethanol), were obtained from 4.17 gm of N-[2-(3 '-phenyl-propionyl)- l ,2,3 ,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester (m. p. 138141C.) and 1.40 gm ofcyclopentylamine. Analysis: C H N 0 S Na; mol. wt. 477.6

Calculated: C 60.36%; H 5.91%; N 8.80%

Found: C 60.30%; H 5.99%; N 8.84%

EXAMPLE 49 Using a procedure analogous to that described in Ex- 28 ample 46, 1.3 gm of the sodium salt of 2-(2'-phenylpropionyl)-1,2,3 ,4-tetrahydro-7-(N"4-methylcyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 227-228C. (from ethanol), were obtained from 4.00 gm of N[2-(2-phenyl-propionyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]-carbamic acid ethyl ester and 1.02 gm of 4-methyl-cyclohexylamine. Analysis: C H N 0 S Na; mol. wt. 505.6

Calculated: C 61.76%; H 6.38%; N 8.31% Found: C 61.60%; H 6.60%; N 8.10%

EXAMPLE 50 Using a procedure analogous to that described in Example 46, 0.8 gm of the sodium salt of 2-(2'-phenylpropionyl)-1,2,3,4-tetrahydro-7-[N-adamantyl-(1)- ureido-N-sulfonyl]-isoquinoline, m. p. 225229C. (from ethanol), were obtained from 5.05 gm of N-[2-(2 '-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-7- sulfonyl]-carbamic acid ethyl ester and 2.50 gm of adamantyl-(l )-amine hydrochloride and 1.35 g of triethylamine.

Analysis: C H N 0., S Na; mol. wt. 543.7

Calculated: C 3064.07%; H 6.30%; N 7.73%

Found: C 63.80%; H 6.30%; N 7.58%

EXAMPLE 51 EXAMPLE 52 Using a procedure analogous to that described in Example 46, 2.05 gm of the sodium salt of 2-(3'-phenylbutyryl)-1,2,3,4-tetrahydro-7-[N-adamantyl-( l ureido-N-sulfonyl]-isoquinoline, m. p. 263-265C. (decomp.; from ethanol), were obtained from 4.5 gm of N-[ 2-( 3 -phenyl-butyryl)-1,2,3 ,4-tetrahydroisoquinoline-7-sulfonyll-carbamic acid ethyl ester (m. p. -108C.) and 1.74 gm of adamantyl-(l )-amine. Analysis: C H N 0 S Na; mol. wt. 557.7

Calculated: C 64.62%; H 6.51%; N 7.54%

Found: C 64.30%; H 6.83%; N 7.56%

EXAMPLE 53 Using a procedure analogous to that described in Example 46, 0.8 gm of the sodium salt of 2-(2-p-chlorophenyl-propionyl l ,2,3 ,4-tetrahydro-7-(N '-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 228-230C. (decomp.), were obtained from 4.51 gm of glass-like N-[2-(2'-p-chlorophenyl-propionyl)-l ,2,3 ,4- tetrahydro-isoquinoline-7-sulfonyl]-carbamic ethyl ester and 1.10 gm of cyclohexylamine.

EXAMPLE 54 2-(2-p-Chlorophenyl-propionyl)-1,2,3 ,4-tetrahydro-7- (N-cyclohexyl-ureido-N-sulfonyl)-isoquinoline A solution of 4.23 gm (11.2 millimols) of 2-(2-pacid 29 chlorophenyl-propionyl)-1,2,3 ,4-tetrahydro-isoquinoline-7-sulfonamide (m. p. 1471 50C.) and 1.26 gm (11.2 millimols) of potassium tert.butylate in 30 ml of anhydrous dimethylformamide was added dropwise at to +C. to 1.50 gm (11.2 millimols) of cyclohexyl isocyanate. Thereafter, the mixture was stirred for 2 hours at 0 to +5C. and then filtered, and the filtrate was acidified with 2N HCl. The greasy precipitate formed thereby was collected by vacuum filtration and dissolved in ethylacetate, and the resulting solution was washed with water, dried over sodium sulfate and evaporated. The residue was purified by column-chr0- matography on silicagel (solvent system cyclohexane acetone glacial acetic acid 40:20:04) and recrystallization from a mixture of ethylacetate and ether (2:1). 3.4 gm of colorless 2-(2'-p-chlorophenyl-propionyl)- 1,2,3 ,4-tetrahydro-7-( N l-cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 1 -1 C., were obtained. Analysis: C H Cl N O, S; mol. wt. 504.0

7 Calculated: C 59.60%; H 6.00%; N 8.34%

Found: C 59.40%; H 6.17%; N 8.44%

One gm (1.985 millimols) of the 2-acyl-7-ureido-sulfonyl-tetrahydroisoquinoline thus obtained was dissolved in 2 ml of absolute ethanol, and 1.985 ml of 1N sodium hydroxide were added. The mixture was evaporated to dryness, and the residue was caused to crystallize by treating it with a mixture of benzene and acetone. The colorless crystalline product was collected by vacuum filtration, washed with ethanol, acetone and ether, and dried at 70C. in a vacuum of 0.1 mm Hg, yielding 1.0 gm of the sodium salt of 2-(2'- p-chlorophenyl-propionyl)-1,2,3 ,4-tetrahydro-7-( N cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. 227-23lC. (decomp.).

Analysis: C H Cl N 0 S Na; mol. wt. 526.1

Calculated: C 57.10%; H 5.56 N 7.99%

Found: C 57.20%; H 5.62%; N 7.97%

EXAMPLE 55 Using a procedure analogous to that described in Example 54, the colorless sodium salt of 1,2,3,4- tetrahydro-2-(2'-p-bromophenyl-propionyl)'7-(N'- cyclohexyl-ureido-N-sulfonyl)-isoquinoline, m. p. 222225C., was prepared from 5.20 gm of 2-(2-pbromophenyl-propionyl)-l ,2,3,4-tetrahydro-isoquinoline-7-sulfonamide, (m. p. l46148C.) and 3.70 gm of cyclohexyl isocyan'ate. The yield was 1.68 gm. Analysis: C H Br N 0 S Na; mol. wt. 570.5

Calculated: C 52.63%; H 5.12%; N 7.37%

Found: C 52.40%; H 5.24%; N 7.28%

The free 2-acyl-7-ureidosulfonyl-tetrahydroisoquinoline had a melting point of l09-1 12C.

The compounds according to the present invention, i.e. those embraced by formula I above and their alkali metal or alkaline earth metal salts, have useful pharmacodynamic properties. More particularly, the compounds of the instant invention exhibit very effective hypoglycemic activities at relatively low dosage levels, coupled with low toxicity. (tested on rats according to the method of U.Harding, G.Heinzel, Zeitschrift f.klin. Chem.u.Biochem. 7, 640-643 (1969)).

For pharmaceutical purposes the compounds according to the present invention are administered to warm-blooded animals perorally or parenterally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective dosage unit of the compounds according to the present invention is from 0.0166 to 0.33 mgm/kg, preferably 0.083 mgm/kg body weight.

The following examples illustrate a few hypoglycemic dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 56 Tablets The tablet composition was compounded from the following ingredients:

Sodium salt of l,2,3,4-tetrahydro- 2-(2'-p-bromophenyl-propionyl)-7- (N'-cyclohexyl-ureido-N-sulfonyl)- isoquinoline 5.0 parts Lactose 85.0 parts Com starch 26.0 parts Polyvinylpyrrolidone 3.0 parts Magnesium stearate 1.0 parts Total 120.0 parts Preparation:

The isoquinoline compound was intimately admixed with the lactose and the corn starch, the mixture was EXAMPLE 57 Gelatin Capsules The capsule filler composition was compounded from the following ingredients:

Sodium salt of l,2,3,4-tetrahydro- 2-(2'-p-bromophenyl-propionyl)-7- (N'-cyclohexyl-ureido-N-sulfonyl)- isoquinoline Corn starch, dry

5.0 parts 95.0 parts Total 100.0 parts Preparation:

The ingredients were intimately admixed with each other, the mixture was passed through a 0.75 mm-mesh screen, and mgm-portions of the screened mixture were filled into hard gelatin capsules of suitable size. Each capsule contained 5.0 mgm of the isoquinoline compound and, when administered perorally to a warm-blooded animal of about 60 kg body weight in need of such treatment, produced a very effective hypoglycemic action.

Analogous results were obtained when any one of the other compounds embraced by formula I or an alkali 31 32 metal or alkaline earth metal salt thereof was subyl, diphenyl, a-naphthyl, l,2,3,4-tetrahydrostituted for the particular isoquinoline compound in napthyl-(l),indanyl-(1)orbenzoyl, Examples 56 and 57,especially the following: R is n-butyl, cycloalkyl of five to eight carbon l,2,3,4-Tetrahydro-2-(2'-p-chlorophenyl-propioatoms, alkyl of one to two carbon atoms nyl)-7-(N'-cyclohexyl-ureido-N-sulfonyl)-isoquin- 5 cycloalkyl of five to eight carbon atoms, or adaoline; mantyl-( l g Sodium salt of 1,2,3,4-tetrahydro-2-(2'-p-t0lyl- A is a carbon-to-carbon bond, straight or branched propionyl)-7-(N'-cyclohexyl-ureido-N-sulfonyl)- alkylene of one to five carbon atoms or isoquinoline; monophenyl-(alkylene of one to four carbon Sodium salt of 1,2,3,4-tetrahydro-2-[2-(3",4"- 10 atoms),and

dichlorophenyl)-pr0pionyl]-7-(N'cyclohexyln is l or 2, ureido-N-sulfonyl)-isoquinoline; a non-toxic alkali metal salt thereof, or a non-toxic al- Sodium salt of l,2,3,4-tetrahydro-2-(2-pkaline earth metal salt thereof.

trifluoromethyl-phenyl-propionyl)-7-(N- 2. A compound according to claim 1, which is cyclohexyl-ureido-N-sulfonyl)-isoquinoline; or 1,2,3 ,4-tetrahydro-2-(2'-p-chlorophenyl-propionyl)-7- 2,3,4,5-Tetrahydro-3-(2'-p-bromophenyl-propio- (N-cyclohexyl-ureido-N-sulfonyl)-isoquinoline or the nyl)-7-(N-cyclohexyl-ureido-N-sulfonyl)-1H-3- sodium salt thereof. benzazepine. 3. A compound according to claim 1, which is Likewise, the amount of active ingredient in these il- 1,2,3,4-tetrahydro2-(2'-p-tolyl-propionyl)-7-(N'- lustrative examples may be varied to achieve the cyclo-hexyl-ureido-N-sulfonyl)-isoquino1ine or the dosage unit range set forth above, and the amounts and sodium salt thereof.

nature of the inert pharmaceutical carrier ingredients 4. A compound according to claim 1, which is may be varied to meet particular requirements. 1,2,3,4-tetrahydro-2-[2'-(3",4"-dichlorophenyl)- While the present invention has been illustrated with pr0pionyl]-7-(N'-cyc1ohexyl-ureido-N-sulfonyl)- the aid of certain specific embodiments thereof, it will isoquinoline or the sodium salt thereof.

be readily apparent to others skilled in the art that the 5. A compound according to claim 1, which is invention is not limited to these particular embodi- 1,2,3,4-tetrahydro-2-(2'-p-trifluoromethyl-phenylments, and that various changes and modifications may propionyl)-7-(N'-cyclohexyl-ureido-N-sulfonyl)- be made without departing from the spirit of the invenisoquinoline or the sodium salt thereof. tion or the scope of the appended claims. compound accordmg to clam ,whlch we claim: 2,3,4,5-tetrahydro-3-(2-p-bromopheny1-prop|onyl)-7- 1' A compound of the formula (N'-cyclohexyl-ureido-N-sulfonyl)-1H-3-benzazepine or the sodium salt thereof. 7. A compound according to claim 1, which is E l l,2,3,4-tetrahydro-2-(2'-p-bromophenyl-propionyl)-7- 1t11tcN R (N-cyclohexyl-ureido-N-sulfonyl)-isoquinoline or the 4 sodium salt thereof.

2 8. A compound according to claim 1, which is wherein l,2,3,4-tetrahydro-2-(2'-phenyl-propionyl)-7-(N- R1 is phenyl, alkoxy of one to three carbon atoms 4O cyclohexyLureido-N-sulfonyl)-isoquinoline or the sodiphenyl, tolyl, trifluoromethyl-phenyl, monohaloum salt thereof phenyl, dihalo-phenyl, 2-methoxy-5-chloro-phenj UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION A Patent No. 3,725,388 Dated April 3, 19 73 Wolfgang- Grell et a1 Inventor(s) It is certified that error appears in'the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Insert [30] Foreign Application Priority Data July 1, 1969 Germany P 19 33 388.1

June 4, 1970 Germany P 20 27 436.6

Column 2, line 54 "R" should read R Columns), line 26, ;N" should read Z, same column .3, Formula (XII) should appear as shown belowi g 1 N\(CH2) Column 5, line 67,' "8.-1'4%" should read 8.13% -''j. Column 6, line 64 Vgphenyl-propionyl') should read was then Column 22, line 22, after "3 insert trifluoromethylbenzoyl)- line 59, "c-" shouldread 3 Column 23, line 44, in the formula 1| should read I] 0 v 1 C Column 25, line 53 after "diphenyl" insert ---propionyl Column 28, line 2.3 nc "30" after ,HC n

Signediand sealed this Q-thday of July 1974.

1 mm V Attest:

MCCOY M. GIBSON, JR. j 1c. MARSHALL DANN Attesting Officer Commissioner of Patents USCOMM-DC 6O376-P69 u.s. aovumazm manna ornc: In! o-alI-au,

FORM PC4050 (10-69) 

2. A compound according to claim 1, which is 1,2,3,4-tetrahydro-2-(2''-p-chlorophenyl-propionyl)-7-(N''-cyclohexyl-ureido-N-sulfonyl)-isoquinoline or the sodium salt thereof.
 3. A compound according to claim 1, which is 1,2,3,4-tetrahydro-2-(2''-p-tolyl-propionyl)-7-(N''-cyclo-hexyl-ureido-N -sulfonyl)-isoquinoline or the sodium salt thereof.
 4. A compound according to claim 1, which is 1,2,3,4-tetrahydro-2-(2''-(3'''',4'''' -dichlorophenyl)-propionyl)-7-(N''-cyclohexyl-ureido-N-sulfonyl)-isoquinoline or the sodium salt thereof.
 5. A compound according to claim 1, which is 1,2,3,4-tetrahydro-2-(2''-p-trifluoromethyl-phenyl-propionyl)-7-(N'' -cyclohexyl-ureido-N-sulfonyl)-isoquinoline or the sodium salt thereof.
 6. A compound according to claim 1, which is 2,3,4,5-tetrahydro-3-(2''-p-bromophenyl-propionyl)-7-(N''-cyclohexyl-ureido-N -sulfonyl)-1H-3-benzazepine or the sodium salt thereof.
 7. A compound according to claim 1, which is 1,2,3,4-tetrahydro-2-(2''-p-bromophenyl-propionyl)-7-(N''-cyclohexyl-ureido-N -sulfonyl)-isoquinoline or the sodium salt thereof.
 8. A compound according to claim 1, which is 1,2,3,4-tetrahydro-2-(2''-phenyl-propionyl)-7-(N-cyclohexyl-ureido-N -sulfonyl)-isoquinoline or the sodium salt thereof. 